Ghrelin is a hormone with diverse actions, the most studied of which are its effects on body weight. Our recent work also demonstrates antidepressant-like behavioral effects of ghrelin. As such, ghrelin levels rise not only in association with hunger and fasting, thus leading to stimulation of food intake and conservation of energy stores, but also upon chronic stress. These elevations with stress seem to minimize the depression-like behaviors normally associated with stress, as acute peripheral infusions of ghrelin into wild-type mice induce antidepressant-like behaviors, and as mice lacking ghrelin receptors (growth hormone secretagogue receptor; GHSR) demonstrate even more depression-like behaviors than wild-type mice. Ghrelin rises also mediate the antidepressant-like effects of prolonged caloric restriction. These ghrelin effects presumably occur via interaction with its receptors in one or more of the CNS sites comprising GHSR's well-defined, discrete pattern of expression. For instance, GHSRs are expressed within dopaminergic ventral tegmental area (VTA) neurons that are involved in brain reward circuits and that also play an obligatory role in the development of rodent measures of depression. GHSRs also are highly expressed within the hippocampus, another site with well established effects on mood and antidepressant efficacy. In the current application, we provide studies designed to further explore ghrelin's actions in promoting antidepressant-like behaviors. We will investigate the effects of chronic ghrelin administration and pharmacologic blockade of ghrelin action on these behaviors in both male and female mice. We will employ unique genetically-manipulated mouse models in which GHSR expression can be site-selectively targeted to or deleted from dopaminergic VTA neurons or hippocampal neurons as well as CNS site-specific ghrelin microinjection studies to determine the role of the VTA and hippocampus in ghrelin's antidepressant effects. Finally, we will further explore the mechanism of ghrelin's antidepressant actions by examining the role of brain derived nuclear factor (BDNF) signaling cascades within both VTA and hippocampal circuits. We hope that these studies will uncover new pathways involved in the development of mood disorders, including the depression so closely linked to conditions with known perturbations of ghrelin physiology. PUBLIC HEALTH RELEVANCE: The experiments proposed in this study have been designed to investigate the role ghrelin plays in mood and the responses to chronic stress. It is hoped that these studies will uncover new pathways involved in the development of depression and will result in new therapies to treat mood disorders, and particularly the depression so closely linked to chronic stress and conditions with known perturbations of ghrelin physiology.